Targeted drug delivery via nanoparticles holds great potential for the successful treatment of many deadly diseases such as cancer. PEG-modification is commonly used to prevent nonspecific interactions of the nanoparticles with blood components and nontarget cells. However the ability to achieve high targeting efficiency at the tumor site remains a significant challenge. There are several reports showing a reduction of transfection efficiency and decreased adhesion of phospholipids, liposomes and polymersomes presumably due to shielding of the targeting functional groups by the PEG chains. PEG chain length, grafting density, nanoparticle size and density of functional groups all were found to strongly influence the success of targeting. To analyze the influence of all these factors experimentally is a very complicated and time-consuming task. Computer simulation may considerably aid in this task by analyzing the influence of multiple parameters, thereby guiding the experimental research. The objective of the present proposal is to apply a combined theoretical and experimental approach to gain fundamental understanding of the physical principles of targeting by complex polymer nanoparticles. The central hypothesis is that the ligand valence and the structure of the corona of nanoparticles are the key factors defining the efficiency of site-specific targeting. To test this hypothesis we will carry out research designed to fulfill the following aims: 1) Structural design of a nanoparticle for effective targeting for each of the following concepts: a) using multivalent ligands and b) using short non-functional and long functionalized PEG chains in nanoparticle corona. 2) Design and experimental testing of the optimal PCL-PEG-cRGD nanoparticles for doxorubicih (DOX) delivery. Nanoparticle designs found to be optimal in simulations will be tested experimentally using in vitro binding study and cell uptake study in integrin-expressing and non-expressing melanoma cells. Successful execution of this research will supply an experimental practitioner with specific recommendations concerning the grafting density, PEG chain length, architecture, nanoparticle size and density of functional groups to ensure effective targeting of drug-containing nanoparticles. Because of the exploratory nature of the research some new approaches to drug targeting may be discovered. This knowledge will greatly facilitate the development and implementation of a new generation of drug delivery vehicles for cancer therapy. [unreadable] [unreadable] [unreadable]